Project #1 of the CReATe Consortium seeks to address two specific challenges to therapy development for ALS and related disorders. The first challenge is the etiological and phenotypic heterogeneity of ALS and related disorders. The implication of diverse etiology is that therapeutic approaches, especially those that target upstream biological mechanisms, need to be targeted to subsets of patients with shared etiology and/or biology. Heterogeneity of phenotype (e.g. rates of disease progression or survival) complicates discernment of therapeutic ?signal? amidst the ?noise? of natural variation. With an imminent future of clinical trials that will target specific subsets of patients (e.g. SOD1 and C9ORF72 ALS and SPAST HSP), there is an urgency to quantitative define the natural history of the most common genetic forms of ALS and related disorders. This entails estimating the mean and person-to-person variation in rates of change of the most commonly used outcome measures (e.g. ALSFRS-R, SVC, SPRS). In parallel, we will use anchor-based methods to estimate the minimum clinically important change, from the patient perspective, in these functional measures. The heterogeneity of phenotype, however, extends beyond the motor domain, with increasing recognition that cognitive and behavioral dysfunction are common manifestations of this group of disorders. We will, therefore, also characterize the longitudinal course of cognitive and behavioral dysfunction, relying primarily on the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) and the CReATe Cognitive Behavioral Battery (C2B2) and age- and education-adjusted normative data that we will develop. The second challenge we will address is the low overall rate of patient participation in research. Specifically, we will (a) roll out use the ALS Toolkit in the Epic electronic health record to better capture research quality data in the course of multi- disciplinary patient care; (b) expand initiatives to empower remote collection of outcome data using both mobile smartphone-based technology and home use spirometry devices; and (c) explore the utility of an ALS-specific patient reported outcome (PRO) that has been designed to capture the perspective of patients and their caregivers about what matters most to them. Successful completion of these aims is expected to yield low- burden approaches to assessing outcomes that are important to patients and that are clinically relevant.